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<p>Chemoresistance is the most significant challenge affecting the clinical efficacy of the treatment of patients with gastric cancer (GC). Here we reported that transmembrane protein 160 (TMEM160) suppressed ferroptosis and induced chemoresistance in GC cells. Mechanistically, TMEM160 recruited the E3 ligase TRIM37 to promote K48-linked ubiquitination and degradation of KEAP1, thereby activating NRF2 and transcriptionally upregulating the target genes <i>GPX4</i> and <i>SLC7A11</i> to inhibit ferroptosis. Further in vitro and in vivo experiments demonstrated that the combination of TMEM160 targeting and chemotherapy had a synergistic inhibitory effect on the growth of GC cells, which was partially NRF2-dependent. Moreover, TMEM160 and NRF2 protein levels were markedly overexpressed in GC tissues, and their co-overexpression was an independent factor for poor prognosis. Collectively, these findings indicate that TMEM160, as a pivotal negative regulator of ferroptosis, exerts a crucial influence on the chemoresistance of GC through the TRIM37-KEAP1/NRF2 axis, providing a potential new prognostic factor and combination therapy strategy for patients with GC.</p>

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TMEM160 inhibits KEAP1 to suppress ferroptosis and induce chemoresistance in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月13日

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  • Chunye Huang,
  • Qinru Zeng,
  • Jingyi Chen,
  • Qin Wen,
  • Weilun Jin,
  • Xiaofeng Dai,
  • Ruiwen Ruan,
  • Hongguang Zhong,
  • Yang Xia,
  • Zhipeng Wu,
  • Ruixuan Huang,
  • Jianxi Zhang,
  • Yangyang Yao,
  • Li Li,
  • Wan Lei,
  • Jianping Xiong,
  • Jun Deng

摘要

Chemoresistance is the most significant challenge affecting the clinical efficacy of the treatment of patients with gastric cancer (GC). Here we reported that transmembrane protein 160 (TMEM160) suppressed ferroptosis and induced chemoresistance in GC cells. Mechanistically, TMEM160 recruited the E3 ligase TRIM37 to promote K48-linked ubiquitination and degradation of KEAP1, thereby activating NRF2 and transcriptionally upregulating the target genes GPX4 and SLC7A11 to inhibit ferroptosis. Further in vitro and in vivo experiments demonstrated that the combination of TMEM160 targeting and chemotherapy had a synergistic inhibitory effect on the growth of GC cells, which was partially NRF2-dependent. Moreover, TMEM160 and NRF2 protein levels were markedly overexpressed in GC tissues, and their co-overexpression was an independent factor for poor prognosis. Collectively, these findings indicate that TMEM160, as a pivotal negative regulator of ferroptosis, exerts a crucial influence on the chemoresistance of GC through the TRIM37-KEAP1/NRF2 axis, providing a potential new prognostic factor and combination therapy strategy for patients with GC.